Genetic Variant NM_003483.6:c.249+13219C>T (chr12-65851788-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003483.6(HMGA2):c.249+13219C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0746 in 292,012 control chromosomes in the GnomAD database, including 2,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.11 ( 1802 hom., cov: 32)

Exomes 𝑓: 0.041 ( 225 hom. )

Consequence

HMGA2
NM_003483.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.04

Publications

4 publications found

Variant links:

Genes affected

HMGA2 (HGNC:5009): (high mobility group AT-hook 2) This gene encodes a protein that belongs to the non-histone chromosomal high mobility group (HMG) protein family. HMG proteins function as architectural factors and are essential components of the enhancesome. This protein contains structural DNA-binding domains and may act as a transcriptional regulating factor. Identification of the deletion, amplification, and rearrangement of this gene that are associated with myxoid liposarcoma suggests a role in adipogenesis and mesenchymal differentiation. A gene knock out study of the mouse counterpart demonstrated that this gene is involved in diet-induced obesity. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

HMGA2 links:

HMGA2-AS1 (HGNC:53973): (HMGA2 antisense RNA 1)

HMGA2-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.28 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA2	NM_003483.6 link	c.249+13219C>T		intron_variant	Intron 3 of 4	ENST00000403681.7	NP_003474.1	P52926-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA2	ENST00000403681.7 link	c.249+13219C>T		intron_variant	Intron 3 of 4	1	NM_003483.6	ENSP00000384026.2		P52926-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15944

AN:

152112

Hom.:

1791

Cov.:

show subpopulations

Gnomad AFR

AF:

0.283

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0607

Gnomad ASJ

AF:

0.118

Gnomad EAS

AF:

0.000962

Gnomad SAS

AF:

0.0505

Gnomad FIN

AF:

0.0212

Gnomad MID

AF:

0.0728

Gnomad NFE

AF:

0.0322

Gnomad OTH

AF:

0.0890

GnomAD4 exome

AF:

0.0415

AC:

5799

AN:

139782

Hom.:

225

AF XY:

0.0429

AC XY:

3386

AN XY:

78872

show subpopulations

African (AFR)

AF:

0.243

AC:

615

AN:

2526

American (AMR)

AF:

0.0297

AC:

268

AN:

9022

Ashkenazi Jewish (ASJ)

AF:

0.0943

AC:

340

AN:

3606

East Asian (EAS)

AF:

0.00

AC:

AN:

2528

South Asian (SAS)

AF:

0.0553

AC:

1820

AN:

32920

European-Finnish (FIN)

AF:

0.0254

AC:

187

AN:

7358

Middle Eastern (MID)

AF:

0.0801

AC:

166

AN:

2072

European-Non Finnish (NFE)

AF:

0.0285

AC:

2083

AN:

73084

Other (OTH)

AF:

0.0480

AC:

320

AN:

6666

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

261

521

782

1042

1303

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.105

AC:

15997

AN:

152230

Hom.:

1802

Cov.:

AF XY:

0.102

AC XY:

7627

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.284

AC:

11786

AN:

41498

American (AMR)

AF:

0.0606

AC:

927

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

410

AN:

3472

East Asian (EAS)

AF:

0.000964

AC:

AN:

5186

South Asian (SAS)

AF:

0.0497

AC:

240

AN:

4826

European-Finnish (FIN)

AF:

0.0212

AC:

225

AN:

10594

Middle Eastern (MID)

AF:

0.0850

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0322

AC:

2192

AN:

68030

Other (OTH)

AF:

0.0885

AC:

187

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

653

1306

1960

2613

3266

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0830

Hom.:

202

Bravo

AF:

0.116

Asia WGS

AF:

0.0400

AC:

141

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.73

(source)

DANN

Benign

0.69

PhyloP100

-1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_003483.6:c.249+13219C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over